NOTES
JIarch 1970
327
T.IBLEI CH 0,
CH,O’ Yield,
s
TO.
Rl
s
NO?
SO,
XOZ
PO, SO2 SO? SO2 C=NH
NHz B (COCR3)z NO2 SHz NH(COCH3 ) NH, F
10
CO
F
11
CO
?yT3
1 2
H H
70 28.0 90.0
H
68.4
R?
Crystn solvent
Alp, O C , “ or l ~ p ”, C (mm)
PIIeOH AcOH-H2O
123-124 183- 18.5
(80:20) >
4 1
8
6
s
I
S
0
H NO? SH, N(COCH3)j NH? H.HC1 H H H H
41.0 91 4 23.6 32 0 81 .0 44.8 81.0 40.0
SIeOH MeOH AcOH MeOH EtOH EtOH i-PrOH
218-220 170-172 2003-203 123-124.5 243-245 191-192 197. 3- 199
Cyclohexane Cyclohexane C6H6
Si-69 89-90 12 CO NHz 1.i.j-136 1:, CHz SHz 153-160 1 0 .3 ) 14 It S pfI: EtOH 141-143 0 Mi melting points are uncorrected. Compounds 1-7, 9, 11-13 were analyzed for C, H , S ; 8 wa.3 analJ-zed for K ; and 10 and 13 were analyzed for C, H. -411 analyses were withiii 10.476 of calculated values except 4,C: calcd, 56.01; found, 56.43; and 11, 1: c a l d . 1 :3.41 j found, 12.44; 12.48.
2-Acetylamino-4-diacetylamino-3’,4’,5’-trimethoxydiphenyl sulfone ‘7)was prepared by acetylating 6 in refluxing Acz0, removing .icrO wider reduced pressure, and oxidizing the residue with H202according to the procedure given for 2 except that the reactioii niixtrire was evaporated to dryness under reduced pressure ( b a t h temperature ca. 60”), the residue treatedwith HzO, and the product removed by filtration and purified by crystallization. 2,4-Diamino-3’,4’,5’-trimethoxydiphenylsulfone (8)was prepared by the hydrolyjis of 7 with 6 -V HCI. 4-Fluoro-3’,4’,5‘-trimethoxybenzophenone Ketimine Hydrochloride iS).-The Grignard reagent of p-fluorobromobenzerie (7Y..i g, 0.42 mol:) with 9.2 g (0.4 g-atom) of SIg wabprepared in 300 nil t r f EtJ.1. A solution of :3,4,5-triniethoxybenzonitrile(50.0 g, 0.26 moli i l l 150 ml of dry T H F was added to it slowly. The niixtrire was then brought to reflux and the solvent was replaced b?- an eqriivalent amount of PhMe aiid refluxed for 16 hr. It was cooled, gassed with NH3 for 1 hr, and filtered hot’, the filtrate concentrated to an oil, and the oil dissolved in EtsO and converted iiito the HCI salt. 4-Fluoro-3’,4’,5’-trimethoxybenzophenone(lo).-A mixture of 9 140.0 g, 0.132 mol) and 350 ml of 6 .V HCl was heated on a steam bath for 4 hr. The mixture was cooled and extracted with Et20 t o obtain the oily product which solidified on standing. 4-Azido-3’,4’,5’-trimethoxybenzophenone(ll).-A mixt’ure of 10 ( 5 . 3 g, 0.02 mol), NaN3 (3.3 g, 0.05 mol), 60 ml of DMSO, and 1.5 nil of HzO was heated with stirring a t 100-110” for 16 hr. The mixture was cooled and diluted with HaO, the product ext racted with EtzO, and the EtzOext,ractswere worked up as usual. 4-Amino-3’,4’,5’-trimethoxybenzophenone(12).--A mixture of 11 (3.13 g, 0.01 mol), 0.4 g of 5% Pd-C, and 75 ml of hIeZCO a.as hydrogenated a t room temperature and atmospheric pressure. hfter :3 hr the mixture was filtered and concentrated to give a wlid product. 4-Amino-3’,4’,5’-trimethoxydiphenylmethane(13).--8 mixtiire of 12.HC1 (5.0 g, 0.0155 mol), 0.4 g of 5% Pd-C, 100 ml of LIeOH, and 10 ml of AcOH was hydrogenated a t 5 kg/cm2 for .? hr at room temperature. The mixture was filtered and the filtrate was concentrated to a solid, treated with XaOH solution, aiid extracted with CH2C12. The CH&lz extract, on the usual work-lip, gave a syriip which was purified by distillation.
Synthetic Trypanocides. I. Substituted 1,2,3,4-Tetrahydrocarbazoles1 JORGE GlLLO
P L C C . 4 A S D $EM
31.
.iLBOKICO
Department of Organic Chew istry, School of Pharmacy and of Bitenos d i r e s , A,gentina Biochemistiy, C7nizvrsit~ Receirerl October 6 , 2869
The high incidence of the Chagas-Mazza disease (South American trypano.omiasis) among blood donors in some places makes it difficult to reject infected blood.2 Therefore it is necewiry to add to the blood a trypanocidal substance that must be water soluble, compatible with the anticoagulant solution, and resistent t o sterilization, and which prevents infection of the patient by the blood. So far only colorants3 have been used for this purpo-e, but these have many disadvantages. Since some subqtituted 1.2,3,i-tetrahydrocarbazoles are active against Trypanoso~uac~*uzZ’,~ a series of related new compounds fulfilling the above requirements were prepared in order to teit their trypanocidal activity (Table I). Chemistry.-The lJ2,3,4-tetrahydrocarbazole(THC) and the 6-substituted T H C (I) were prepared by the Fisher indole sgnt hesis6 with the modification described in the Experimental Section for 6-iodo-THC.
(1) This investigation was supported by grants from the Instituto Nacional de Farmacologia y Bromatologia and C S I C T . ( 2 ) J. A. Cerisola and J. 0. Lazzari, .Ibstracts, Segundas Jornadas Entoepidemiolbgicas Argentinas. 1967, p 203. (3) J . Kloetzel, R e i . I w t . M e d . T r o p . S u o Paulo. 3, 254 (1961). Acknowledgment.-This work was supported by U. S. (4) G . C. Vilaseca, J. .4. Cerisola, J. .%. Olarte. and A. Zothner. T’oz Army Medical Research and Development Command Sanguinis, 11, 711 (1966). under Research Contract No. DA-49-193-AID-2869, (5) U. Horlein, German Patent 930,988 (1955); Chem. A b s t ~ . .82, 17288
and is Contribution No. 718 from the Army Research Program on Nalaria.
(1958). (6) C. U. Rogers and B. B. Corson, “Organic Synthesis,” Coll. Vol. John Wiley & Sons, Inc., New York, N. T., 1963, p 884.
IV,
